The proposed application, entitled Precursors and Prognosis of Traumatic Brain Injury in Young to Middle Aged Adults seeks to determine whether single or repeated traumatic brain injuries (TBI) increase risk for later life decline in cognition mood, behavior and daily function. This project leverages already available health, lifestyle, biomarker, genetic, cognitive and neuroimaging data and combines it with proposed acquisition of new TBI data recommended as Common Data Elements (CDE) by the National Institute of Neurological Disorders and Stroke (NINDS). This study marks an initial effort to systematically collect specific NINDS CDE on TBI in a community-based sample. Further, while the concept of developing risk profile scores originated within the Framingham Heart Study and have been widely used, risk profile scores have not been utilized for documenting activities that can lead to impact exposures and TBIs in order to characterize whether those exposures lead to later life consequences. The proposed study will obtain detailed histories of military service, sports participation, and employment to retrospectively assess exposure to impacts, and will also determine prevalence of diagnosed TBI in the Framingham Heart Study Generation 3 (Gen 3; n=4095) and its smaller multi-ethnic Omni Generation 2 (n=410; Omni Gen 2) cohorts. We will then relate these risk factors to available and new computerized measures of cognition to determine whether history of impact exposures and/or diagnosed TBI is associated with cognitive impairment and accelerated decline. We will also examine whether history of impact exposures and/or diagnosed TBI is associated with smaller brain volumes and compromised white matter integrity, particularly in the regions of the brain linked to memory and executive function. Further we will address the question of whether these risk factors are associated with changes in mood, behavior and daily functioning. Finally, we will seek to identify metabolic and inflammatory biomarkers associated with history of impact exposures and/or diagnosed TBI and whether specific genetic markers modify the relationship between TBI and chronic health outcomes. Our focus on the potential long-term consequences of engaging in activities that can lead to impact exposures and TBIs in the general population has significant implications for public health.